Second-Generation Synthesis of (+)-Fastigiatine Inspired by Conformational Studies

Abstract

(+)-Fastigiatine is a complex alkaloid isolated from the alpine club moss Lycopodium fastigatum, most commonly found in New Zealand. It has been the subject of two successful synthetic campaigns. A second-generation route toward fastigiatine was developed to resolve two problematic steps from our initial synthesis. Selective reduction and protection of the C13 ketone improved the yield and reliability of the dibromocarbene ring expansion step. In the prior synthesis, cuprate addition to the C10 enone generated a 1:1 mixture of isomers in an advanced intermediate. Protection of the C13 alcohol with a large silyl group changed the conformational preference of the enone and led to a more selective conjugate addition to produce the desired β-epimer at C10. MacMillan's decarboxylative photoredox addition method proved to be more practical than the prior aminomethyl cuprate addition chemistry. The second-generation synthesis is longer than the original but improves the selectivity and reproducibility of the overall route.

Total Synthesis of (−)‐Himeradine A

“…[27] Minor diastereomers (epimeric at C14 and/or C5) are likely present, but are expected to isomerize to the viable intermediate 19 in the transannular Mannich step. [10] Simply treating diketone 19 with excess CSA in o-DCB at 165 8 8C facilitated rapid global Boc-deprotection, allowing imineformation to occur, followed by the expected transannular Mannich reaction to form the key C14 À C6 bond and completing the C-14 quaternary center. Notably,n oq uinolizidine formation was observed under these conditions, probably due to the protonation and deactivation of the piperidine nitrogen by the excess CSA.…”

“…We planned to complete the quinolizidine assembly in this step. The fastigiatine synthesis used a late‐stage B ‐alkyl Suzuki coupling and a decarboxylative radical 1,4‐addition to assemble the Mannich precursor . To utilize this approach for himeradine A, we envisioned coupling a masked, but fully elaborated, piperidine subunit 5 with the bromoenone 4 .…”

“…Ther elative configuration at C17 and C10' was assigned by the NOESY correlations between H17/H10', H11'/H8',H11'/H6',and H11'/H2'.The absolute configuration of the molecule was assigned based on analogy to the structure of fastigiatine. [9] Our approach towards (À)-himeradine Ab uilt on our first-and second-generation syntheses of fastigiatine, [10] and is outlined in Figure 2. Thefastigiatine core would be assembled by at ransannular Mannich reaction from intermediate 3, which was inspired by the proposed biosynthesis.…”

“…Bromoenone 4 was ak ey intermediate in the fastigiatine synthesis and delivers all but three of the atoms in the core structure after the Mannich transformation. [10] It is prepared in four steps from (R)-5-methylcyclohex-2-enone. [10] The configuration of the allyl amine in 5 would arise from ac atalyst-controlled Overman rearrangement.…”

“…[10] It is prepared in four steps from (R)-5-methylcyclohex-2-enone. [10] The configuration of the allyl amine in 5 would arise from ac atalyst-controlled Overman rearrangement. [12] Thee nantiopure dialkyl piperidine 6 precursor could be prepared with an auxiliary-controlled hydrogenation, [13] or ac lassic salt resolution of the racemic material.…”